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Ancient hot and cold genes and chemotherapy resistance emergence

Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Robert A. Gatenby, Hyunsung John Kim, Nader Pourmand, Kimberly Bussey, Paul C. W. Davies, James C. Sturm, and Robert H. Austin
PNAS published ahead of print August 3, 2015 https://doi.org/10.1073/pnas.1512396112
Amy Wu
aPrinceton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544;
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Qiucen Zhang
bDepartment of Physics, University of Illinois at Urbana–Champaign, Urbana, IL 61801;
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Guillaume Lambert
cDepartment of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637;
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Zayar Khin
dMoffitt Cancer Center, Tampa, FL 33612;
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Robert A. Gatenby
dMoffitt Cancer Center, Tampa, FL 33612;
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Hyunsung John Kim
eDepartment of Bioengineering, University of California, Santa Cruz, CA 95064;
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Nader Pourmand
eDepartment of Bioengineering, University of California, Santa Cruz, CA 95064;
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Kimberly Bussey
fThe Biodesign Institute, Arizona State University, Tempe, AZ 85287;
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Paul C. W. Davies
gBeyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ 85287;
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James C. Sturm
aPrinceton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544;
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Robert H. Austin
hDepartment of Physics, Princeton University, Princeton, NJ 08544
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  • For correspondence: austin@princeton.edu
  1. Contributed by Robert H. Austin, June 26, 2015 (sent for review May 27, 2014; reviewed by Eshel Ben-Jacob2 and Michael W. Deem)

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Significance

There are two broad components of information dynamics in cancer evolution. One involves permanent changes in which genes are subject to gain or loss-of-function substitutions. This is well established and the main focus of cancer research. The other component is the information in the human genome and preservation of that content. The cancer cell potentially has access to all of this and can upregulate or downregulate any number of strategies used for survival and proliferation during embryogenesis, development, and normal adaptation to environmental stresses. We suggest that nonsubstituted genes may be critical targets for chemotherapy; these nonmutated genes may be the most fundamental ones for preservation of cancer cell fitness, especially if their expression level changes.

Abstract

We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.

  • cancer
  • emergence
  • ancient genes
  • cold
  • hot

Footnotes

  • ↵1To whom correspondence should be addressed. Email: austin{at}princeton.edu.
  • ↵2Deceased June 5, 2015.

  • Author contributions: A.W., Q.Z., G.L., R.A.G., N.P., P.C.W.D., J.C.S., and R.H.A. designed research; A.W. and R.H.A. performed research; A.W., Z.K., R.A.G., K.B., and R.H.A. contributed new reagents/analytic tools; A.W., Q.Z., H.J.K., N.P., K.B., P.C.W.D., J.C.S., and R.H.A. analyzed data; and A.W., G.L., R.A.G., K.B., P.C.W.D., J.C.S., and R.H.A. wrote the paper.

  • Reviewers: E.B.-J., Tel Aviv University; and M.W.D., Rice University.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1512396112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Ancient hot and cold genes in cancer
Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Robert A. Gatenby, Hyunsung John Kim, Nader Pourmand, Kimberly Bussey, Paul C. W. Davies, James C. Sturm, Robert H. Austin
Proceedings of the National Academy of Sciences Aug 2015, 201512396; DOI: 10.1073/pnas.1512396112

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Ancient hot and cold genes in cancer
Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Robert A. Gatenby, Hyunsung John Kim, Nader Pourmand, Kimberly Bussey, Paul C. W. Davies, James C. Sturm, Robert H. Austin
Proceedings of the National Academy of Sciences Aug 2015, 201512396; DOI: 10.1073/pnas.1512396112
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